The abnormal pattern of visual evoked potentials in rabbits with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembles that associated with coma induced by a barbiturate, a benzodiazepine or a -amino-butyric acid (GABA) agonist. As these drugs induce neural inhibition by interacting with binding sites on the GABA receptor complex on postsynaptic neural membranes, these findings suggest that neuronal activity in HE may be similar to the neuronal inhibition induced by GABA. Outside the CNS the main source GABA is gut bacteria and the main site of its catabolism is the liver. When FHF was induced in rabbits the onset of HE was preceded by a marked increase in the plasma levels of GABA-like activity and by nonspecific increase in the permeability of the blood brain barrier (BBB). FHF was associated with significant increases in the densities of brain receptors for the inhibitory amino acid neurotransmitters, GABA and glycine, and for benzodiazepines. FHF was also associated with significant decreases in the densities of brain receptors for the excitatory amino acid neurotransmitters, glutamate and aspartate. FHF was not associated with any change in the densities of brain receptors for four non-amino acid neurotransmitters. In FHF there is an increase in the content of cholesterol and phospholipid relative to that of protein in brain synaptic membranes. These findings suggest that as the liver fails: 1) impaired hepatic metabolism of GABA leads to an increase of gut-derived GABA in plasma and 2) plasma GABA gains access to the brain through a permeable BBB and induces neural inhibition. Changes in the composition of neural membranes and neurotransmitter receptors in liver failure may render the brain less sensitive to excitatory amino acid neurotransmitters and more sensitive to inhibitory amino acid neurotransmitters.